Increased immunogen valency improves the maturation of vaccine-elicited HIV-1 VRC01-class antibodies

Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be a key component of an effective HIV-1 vaccine. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naive B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-class antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses. AUTHOR SUMMARYPA performed ELISA, B cell sorting, BCR sequencing analysis, oversaw the analysis of all immunochemical assays, interpreted the results and wrote the manuscript; AK processed tissues from immunized animals, performed B cell staining, and generated mAbs; KRS performed BLI and BCR sequencing; AM performed BCR sequencing; DR and FAM performed phylogenetic analysis and contributed to writing the manuscript; AR performed ELISA and processed tissues from immunized animals, ABS expressed and purified recombinant Envs; LKS expressed and purified mVRC01 mAb; XS and DM performed neutralization assays; LS conceived and oversaw the study and wrote the manuscript.